食管癌恶性程度高治疗效果差，目前缺乏靶向治疗和精准医疗。食管癌发生发展可分为起始，促进，演化，发展，异质性和转移等多阶段。我们前期工作发现甲基苄基亚硝胺(NMBzA)可特异性地诱导食管上皮发生癌变。我们已利用NMBzA成功构建大鼠食管癌模型，在组织病理学上与人类食管鳞癌病理形态一致，可分为正常上皮-轻度不典型增生-乳头状瘤-中到重度不典型增生-癌这几个阶段。但这一方法周期长，诱癌率低。本项目将在应用NMBzA作为起始剂给药诱癌基础上，增加促癌物沙利度胺的使用，最终建立周期短，成功率高和稳定性强的化学致癌物诱导的大鼠食管癌动物模型。以此动物模型为基础，对得到各阶段组织样本进行测序分析，寻找食管癌的驱动基因，同时对比人食管癌的测序结果，阐明食管癌发生发展中各阶段的分子机制，并应用人食管癌组织芯片等进行验证，为发现与食管癌发生发展相关的潜在靶点，实现食管癌的早期诊断和精准医疗奠定基础。

Esophageal cancer has high malignancy rate and poor treatment outcome. Until now, there have few target therapies and precision medicines for esophageal cancer. The etiology and development of esophageal cancer can be phased into initiation, promotion, evolution, progression, heterogenesis, metastasis and so on. Our lab has previously found N-nitrosomethylbenzylamine with an organotropism for the esophagus can induce the carcinogenesis of esophageal epithelium. We also have established rat esophageal carcinogenesis model. The histopathology of cancer induced by NMBzA in the rat esophagus are similar to human ESCC origin, with stages from normal epithelium, low grade dysplasia, papilloma, moderate or high grade dysplasia to squamous cell carcinoma. However, this method has long carcinogenesis cycle and low rate. So, we will use NMBzA as the first carcinogen for the first stage and establish a multiple-stage chemical carcinogenesis model which has short cycle, high success rate and stability. Using this animal model, we can find driver genes of esophageal cancer in each stage by sequencing analysis of the tissue samples. Combining with the sequencing analysis of human beings, we will illuminate the molecular events in each stages of the carcinogenesis of esophageal epithelium. Then we will identify the driver genes of human esophageal cancer by tissue chips and provide molecular targets for early-stage diagnosis and precision therapy of human esophageal cancer.